Lysosome Membrane Permeabilization and Disruption of the Molecular Target of Rapamycin (mTOR)-Lysosome Interaction Are Associated with the Inhibition of Lung Cancer Cell Proliferation by a Chloroquinoline Analog.
Identifieur interne : 000669 ( Main/Exploration ); précédent : 000668; suivant : 000670Lysosome Membrane Permeabilization and Disruption of the Molecular Target of Rapamycin (mTOR)-Lysosome Interaction Are Associated with the Inhibition of Lung Cancer Cell Proliferation by a Chloroquinoline Analog.
Auteurs : Juan Sironi [États-Unis] ; Evelyn Aranda [États-Unis] ; Lars Ulrik Nordstr M [États-Unis] ; Edward L. Schwartz [États-Unis]Source :
- Molecular pharmacology [ 1521-0111 ] ; 2019.
Descripteurs français
- KwdFr :
- Apoptose (), Autophagie (), Chloroquine (pharmacologie), Chloroquinoléinols (pharmacologie), Humains, Lignée cellulaire tumorale, Lysosomes (), Lysosomes (métabolisme), Membranes (), Perméabilité (), Phosphorylation (), Prolifération cellulaire (), Sérine-thréonine kinases TOR (métabolisme), Transduction du signal (), Tumeurs du poumon (métabolisme), Tumeurs du poumon (traitement médicamenteux).
- MESH :
- métabolisme : Lysosomes, Sérine-thréonine kinases TOR, Tumeurs du poumon.
- pharmacologie : Chloroquine, Chloroquinoléinols.
- traitement médicamenteux : Tumeurs du poumon.
- Apoptose, Autophagie, Humains, Lignée cellulaire tumorale, Lysosomes, Membranes, Perméabilité, Phosphorylation, Prolifération cellulaire, Transduction du signal.
English descriptors
- KwdEn :
- Apoptosis (drug effects), Autophagy (drug effects), Cell Line, Tumor, Cell Proliferation (drug effects), Chloroquine (pharmacology), Chloroquinolinols (pharmacology), Humans, Lung Neoplasms (drug therapy), Lung Neoplasms (metabolism), Lysosomes (drug effects), Lysosomes (metabolism), Mechanistic Target of Rapamycin Complex 1 (metabolism), Membranes (drug effects), Permeability (drug effects), Phosphorylation (drug effects), Signal Transduction (drug effects), TOR Serine-Threonine Kinases (metabolism).
- MESH :
- chemical , metabolism : Mechanistic Target of Rapamycin Complex 1, TOR Serine-Threonine Kinases.
- chemical , pharmacology : Chloroquine, Chloroquinolinols.
- drug effects : Apoptosis, Autophagy, Cell Proliferation, Lysosomes, Membranes, Permeability, Phosphorylation, Signal Transduction.
- drug therapy : Lung Neoplasms.
- metabolism : Lung Neoplasms, Lysosomes.
- Cell Line, Tumor, Humans.
Abstract
Lysosomes degrade cellular proteins and organelles and regulate cell signaling by providing a surface for the formation of critical protein complexes, notably molecular target of rapamycin (mTOR) complex 1 (mTORC1). Striking differences in the lysosomes of cancer versus normal cells suggest that they could be targets for drug development. Although the lysomotropic drugs chloroquine (CQ) and hydroxychloroquine (HCQ) have been widely investigated, studies have focused on their ability to inhibit autophagy. We synthesized a novel compound, called EAD1, which is structurally related to CQ but is a 14-fold more potent inhibitor of cell proliferation. Here we find that EAD1 causes rapid relocation, membrane permeabilization (LMP), and deacidification of lysosomes, and it induces apoptosis and irreversibly blocks proliferation of human lung cancer H460, H520, H1299, HCC827, and H1703 cells. EAD1 causes dissociation of mTOR from lysosomes and increases mTOR's perinuclear versus cytoplasmic localization, changes previously shown to inactivate mTORC1. The effect on mTOR was not seen with HCQ, even at >10-fold greater concentrations. Phosphorylation of a downstream target of mTORC1, ribosomal protein S6, was inhibited by EAD1. Although EAD1 also inhibited autophagy, it retained full antiproliferative activity in autophagy-deficient H1650 lung cancer cells, which have a biallelic deletion of Atg7, and in H460 Atg7-knockout cells. As Atg7 is critical for the canonical autophagy pathway, it is likely that inhibition of autophagy is not how EAD1 inhibits cell proliferation. Further studies are needed to determine the relationship of LMP to mTORC1 disruption and their relative contributions to drug-induced cell death. These studies support the lysosome as an underexplored target for new drug development.
DOI: 10.1124/mol.118.113118
PubMed: 30409790
Affiliations:
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Le document en format XML
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Schwartz</name><affiliation wicri:level="1"><nlm:affiliation>Departments of Medicine (Oncology) (J.S., E.A., E.L.S.) and Biochemistry (L.U.N.), Albert Einstein College of Medicine and the Einstein Cancer Center, Bronx, New York edward.schwartz@einstein.yu.edu.</nlm:affiliation><country wicri:rule="url">États-Unis</country><wicri:regionArea>Departments of Medicine (Oncology) (J.S., E.A., E.L.S.) and Biochemistry (L.U.N.), Albert Einstein College of Medicine and the Einstein Cancer Center, Bronx</wicri:regionArea><wicri:noRegion>Bronx</wicri:noRegion></affiliation></author></analytic><series><title level="j">Molecular pharmacology</title><idno type="eISSN">1521-0111</idno><imprint><date when="2019" type="published">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Apoptosis (drug effects)</term><term>Autophagy (drug effects)</term><term>Cell Line, Tumor</term><term>Cell Proliferation (drug effects)</term><term>Chloroquine (pharmacology)</term><term>Chloroquinolinols (pharmacology)</term><term>Humans</term><term>Lung Neoplasms (drug therapy)</term><term>Lung Neoplasms (metabolism)</term><term>Lysosomes (drug effects)</term><term>Lysosomes (metabolism)</term><term>Mechanistic Target of Rapamycin Complex 1 (metabolism)</term><term>Membranes (drug effects)</term><term>Permeability (drug effects)</term><term>Phosphorylation (drug effects)</term><term>Signal Transduction (drug effects)</term><term>TOR Serine-Threonine Kinases (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Apoptose ()</term><term>Autophagie ()</term><term>Chloroquine (pharmacologie)</term><term>Chloroquinoléinols (pharmacologie)</term><term>Humains</term><term>Lignée cellulaire tumorale</term><term>Lysosomes ()</term><term>Lysosomes (métabolisme)</term><term>Membranes ()</term><term>Perméabilité ()</term><term>Phosphorylation ()</term><term>Prolifération cellulaire ()</term><term>Sérine-thréonine kinases TOR (métabolisme)</term><term>Transduction du signal ()</term><term>Tumeurs du poumon (métabolisme)</term><term>Tumeurs du poumon (traitement médicamenteux)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Mechanistic Target of Rapamycin Complex 1</term><term>TOR Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Chloroquine</term><term>Chloroquinolinols</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Apoptosis</term><term>Autophagy</term><term>Cell Proliferation</term><term>Lysosomes</term><term>Membranes</term><term>Permeability</term><term>Phosphorylation</term><term>Signal Transduction</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Lung Neoplasms</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Lung Neoplasms</term><term>Lysosomes</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Lysosomes</term><term>Sérine-thréonine kinases TOR</term><term>Tumeurs du poumon</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Chloroquine</term><term>Chloroquinoléinols</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Tumeurs du poumon</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Cell Line, Tumor</term><term>Humans</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Apoptose</term><term>Autophagie</term><term>Humains</term><term>Lignée cellulaire tumorale</term><term>Lysosomes</term><term>Membranes</term><term>Perméabilité</term><term>Phosphorylation</term><term>Prolifération cellulaire</term><term>Transduction du signal</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Lysosomes degrade cellular proteins and organelles and regulate cell signaling by providing a surface for the formation of critical protein complexes, notably molecular target of rapamycin (mTOR) complex 1 (mTORC1). Striking differences in the lysosomes of cancer versus normal cells suggest that they could be targets for drug development. Although the lysomotropic drugs chloroquine (CQ) and hydroxychloroquine (HCQ) have been widely investigated, studies have focused on their ability to inhibit autophagy. We synthesized a novel compound, called EAD1, which is structurally related to CQ but is a 14-fold more potent inhibitor of cell proliferation. Here we find that EAD1 causes rapid relocation, membrane permeabilization (LMP), and deacidification of lysosomes, and it induces apoptosis and irreversibly blocks proliferation of human lung cancer H460, H520, H1299, HCC827, and H1703 cells. EAD1 causes dissociation of mTOR from lysosomes and increases mTOR's perinuclear versus cytoplasmic localization, changes previously shown to inactivate mTORC1. The effect on mTOR was not seen with HCQ, even at >10-fold greater concentrations. Phosphorylation of a downstream target of mTORC1, ribosomal protein S6, was inhibited by EAD1. Although EAD1 also inhibited autophagy, it retained full antiproliferative activity in autophagy-deficient H1650 lung cancer cells, which have a biallelic deletion of Atg7, and in H460 Atg7-knockout cells. As Atg7 is critical for the canonical autophagy pathway, it is likely that inhibition of autophagy is not how EAD1 inhibits cell proliferation. Further studies are needed to determine the relationship of LMP to mTORC1 disruption and their relative contributions to drug-induced cell death. These studies support the lysosome as an underexplored target for new drug development.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>État de New York</li></region></list><tree><country name="États-Unis"><region name="État de New York"><name sortKey="Sironi, Juan" sort="Sironi, Juan" uniqKey="Sironi J" first="Juan" last="Sironi">Juan Sironi</name></region><name sortKey="Aranda, Evelyn" sort="Aranda, Evelyn" uniqKey="Aranda E" first="Evelyn" last="Aranda">Evelyn Aranda</name><name sortKey="Nordstr M, Lars Ulrik" sort="Nordstr M, Lars Ulrik" uniqKey="Nordstr M L" first="Lars Ulrik" last="Nordstr M">Lars Ulrik Nordstr M</name><name sortKey="Schwartz, Edward L" sort="Schwartz, Edward L" uniqKey="Schwartz E" first="Edward L" last="Schwartz">Edward L. Schwartz</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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